There is a great need world-wide for transplantable organs such as heart, kidney, liver, and pancreas. In the case of a single kidney or a partial pancreas transplant, it is sometimes possible to locate a living donor with immunological markers compatible with the transplant recipient, although organ donation by a living donor involves great risk and possible deleterious health effects for the donor. In all other cases, the organ donation must come from a high quality, heart-beating human cadaver, and again there must be a good immunological match between the donor and the recipient. Patients in need of an organ transplant often must be on a waiting list for longer than one year, and many patients die before a suitable organ becomes available.
The term "HLA" stands for Human Leucocyte Antigens which are expressed on the surface of most blood and tissue cells. Every person has a set of six HLA antigens which define his tissue type. Anti-HLA antibodies against foreign HLA antigens are acquired by a patient through multiple blood transfusions and pregnancies. These cytotoxic anti-bodies can cause hyperacute rejection of a transplanted organ despite immunosuppressive therapy.
If the recipient of a transplanted organ has cytotoxic anti-HLA antibodies against the tissue of the donor organ, hyperacute rejection of the donor organ follows within minutes to 48 hours after transplant. Hyperacute rejection normally occurs after transplants of certain types of immunologically mismatched allografts (human to human) and xeno-grafts (animal to human).
In choosing a suitable organ for transplant to a human subject, every attempt is made to locate a human donor organ having an ABO blood type and HLA haplotypes which match those of the recipient. Thus, the recipient is not expected to have cytotoxic anti-HLA antibodies against these potentially antigenic molecules, since they are self-antigens. However, a small number of patients in need of organ transplant carry cytotoxic anti-HLA antibodies against several HLA molecules, sometimes including their own HLA molecules. These patients are known as "sensitized" or "hyper-sensitized". Often, a sensitized patient has antibodies against so many different HLA molecules that it is not possible to locate a donor organ that would not be in danger of hyperacute rejection.
The "hyperacute rejection reaction" occurs when the recipient's immune system attacks and destroys the transplanted organ within minutes to hours, typically within 48 hours after transplant. Even when the recipient receives immunosuppressive therapy, hyperacute rejection is not ameliorated.
The hyperacute rejection reaction is thought to occur as a result of pre-formed antibodies in the blood of the recipient which recognize and bind to antigens in the tissue of the donor organ once the transplanted organ is in place and is perfused with the blood of the recipient. When the antibodies bind to endothelial cells of the donor organ blood vessels, they stimulate the deposition of complement proteins, which also originate from the blood of the recipient. Antibody/complement deposition is thought to initiate the "classical" pathway of complement action, which ultimately leads to disruption of the endothelial cell lining of the blood vessels of the donor organ (In: Immunology, Eds: Roitt, I. M., et al, J.B. Lippincott Co, Philadelphia, 1989, Chapter 13, pages 13.1-13.16). The hyperacute rejection reaction results in a necrotic donor organ within minutes to hours after xenotransplant. It has been hypothesized that necrosis of the donor organ results from "activation" of its endothelial cells, which in turn leads to interstitial hemorrhage, inflammation, edema, and small vessel thrombosis (Platt, J. L., et al., Immunology Today 11:450-456, 1990).
An analogy to the hyperacute rejection reaction can be seen in the transplant of ABO-mismatched organs from human donor to human recipient. A recipient with type O blood, for instance, is expected to have preformed anti-A and anti-B antibodies in his blood. Usually, every attempt is made to locate a donor organ well-matched for both ABO blood type and HLA haplotype. However, in certain situations, an ABO-mismatched organ from an HLA-matched donor is the best or only organ available for transplant. In attempts to prevent hyperacute rejection when ABO-mismatched organs were transplanted, pre-formed anti-A/anti-B antibodies were removed from the recipients, blood using extracorporeal perfusion of the recipients' plasma over synthetic A/B blood group antigens covalently linked to silica. Successful kidney and bone marrow transplants were reported using this procedure (Bannett, A. D., et al., Transplant. Proc. 1987 XIX:4543-4546; Bensinger, W. I., et al., Transplantation 1982 33:427-429; U.S. Pat. No: 4,137,401; European patent no: 89311540.2).
It was found that certain pre-formed antibodies in humans bind to carbohydrate residues on foreign antigens. In particular, the antigenic blood group substances A and B bear trisaccharides, which have been chemically synthesized. In a baboon/baboon model for ABO-mismatched heart transplant, the recipient was first administered intravenous A or B trisaccharide on the theory that the trisaccharide would form a "neutralizing" complex with the preformed anti-A or anti-B antibody, thereby preventing hyperacute rejection. When continuous A/B antigen treatment was combined with high-dose immunosuppression, hyperacute rejection was ameliorated in the majority of experiments (Cooper, D. K. C., et al., Transplant. Proc. 24:566-571, 1992).
It has been proposed that immunoglobulins be removed from the blood of an organ recipient when hyperacute rejection of the transplanted organ would otherwise be expected to occur. Immunoglobulin can be removed non-specifically by plasmapheresis. Conventional plasmapheresis, or plasma exchange, results in loss of blood volume, recipient sensitization, and activation of the complement and clotting systems. These side effects of plasmapheresis are somewhat alleviated by volume replacement with pooled preparations of fresh frozen plasma, human albumin, immunoglobulin, and/or a type of bulking agent such as starch. Coagulation factors, platelets, and anti-thrombotic factors must also be replaced. This treatment carries the risk of virus transfer from the pooled human preparations, as well as the risk of anaphylactic reaction to foreign substances. Plasmapheresis does not appear to be either practical or safe for immediate pre-transplant or post-transplant use because of the risk of excessive bleeding.
There has been considerable interest in non-specific antibody removal for indications other than organ transplant, mainly. for the treatment of autoimmune disease. One method for non-specific antibody removal involves perfusing the autoimmune subject's plasma over a column coupled with Protein A from Staphylococcus aureus. Protein A, a major component of the cell wall of S. aureus, has a high affinity for a portion of the Fc-region of sub-classes 1, 2, and 4 of immunoglobulin G (IgG.sub.1, IgG.sub.2, IgG.sub.4) (Dantal, J., et al., New England J. Med.550:7-14, 1994; Nilsson, I. M., et al., Blood 58:38-44, 1981; Palmer, A., et al., The Lancet Jan. 7, 1989, pp.10-12). The Protein-A coupled columns have also been used for the non-specific removal of anti-HLA antibodies from hypersensitized patients who are in need of a kidney transplant. These patients typically suffer from idiopathic nephrotic syndrome (INS). They commonly suffer a relapse of INS soon after transplantation of even the most well-matched donor kidney, thus practically excluding them from the possibility of having any kind of currently available kidney transplant. The efficacy of the Protein A column treatment in several INS patients after kidney transplant was reported (Dantal,et al, supra; Palmer, et al., supra).
It has been proposed to treat autoimmune disease by removal of a significant portion of the patient's immunoglobulins using a column coupled to antibodies directed against human immunoglobulin. Use of such columns in the treatment of auto-immune disease has been suggested as follows: Muller-Derlich, J., et al., Artificial Organs 17 (6):abs. 330 and 339, June 1993; Muller-Derlich, J., et al., Transfusion Medicine 3 (suppl.1):abs. PS20, September 1993; Muller-Derlich, J., et al. Immunobiology 189 (1-2): p.237, Abs. R.9, Sep. 30-Oct. 2, 1993; du Moulin, A., et al., Blood Purif 11:145-149, 1993 (library receipt date=Nov. 17, 1993); Koll, R. et al, 23. CONGRESS OF THE INTERNATIONAL SOCIETY OF BLOOD TRANSFUSION, Jul. 3-8, 1994, Amsterdam-Rai.
It has been proposed that, even if antibodies were removed from the recipient's blood, it would still be necessary to inactivate or remove complement to prevent a hyperacute rejection reaction after transplanting a human organ in danger of being hyperacutely rejected. The administration of cobra venom factor can accomplish the depletion of complement activity by a massive activation of C3, which proceeds to exhaust all subsequent components in the complement cascade. However, the effectiveness of cobra venom factor is short-lived because the recipient rapidly forms neutralizing antibodies against the factor. The administration of cobra venom factor also carries the risk of anaphylactic reaction to the foreign substance.
If the hyperacute rejection phenonenon could be prevented in the early days following transplant, there is a good chance that the patient's immune system would undergo a process of "accommodation" which would diminish or eliminate the reaction between the antibodies and complement of the patient with the endothelial cells of the donor organ (Bach, F. H. et al., Transplant Proc. 23:205-207, 1991.
Another type of organ rejection is observed when the recipient does not have cytotoxic antibodies against the donor organ, but develops antibodies against the foreign tissue over the course of weeks to months after transplant. This would normally occur if, for instance, an HLA-mismatched human organ were transplanted to a human recipient. The newly formed antibodies would cause rejection of the organ in much the same fashion as cytotoxic anti-HLA antibodies cause hyperacute rejection, but the delayed rejection phenomenon is known as "acute rejection".
What is needed is a method to prevent or ameliorate the severity of the hyperacute rejection reaction or acute rejection reaction in the transplantation of a human organ to a human subject who has formed antibodies against the donor organ.